Cardiac adaptation in asphyxiated infants treated with therapeutic hypothermia

Abstract

BACKGROUND:

Hypoxic ischemic encephalopathy (HIE) affects one to two newborns per 1,000 live births and oftentimes involves multi-organ insult. The objectives were to assess the evolution of cardiac function in infants with HIE treated with therapeutic hypothermia using echocardiography (ECHO).

METHODS:

Archived data during the period 2010-2016 was assessed. Amongst the infants with baseline ECHO assessments, a sub-cohort which had assessments in all the three phases (baseline/pre-active cooling [T1], cooling [T2] and rewarming [T3]) was analyzed separately.

RESULTS:

Thirty three infants formed part of the overall cohort, the gestation and birthweight were 39.6 ± 1.6 weeks and 3306 ± 583 g, respectively. Baseline (T1) information noted impaired cardiac performance (right ventricle stroke volume 1.08 ± 0.04 ml/kg, fractional area change [FAC] 24 ± 0.5% and tricuspid annular peak systolic excursion [TAPSE] 7.46 ± 0.11mm). Serial information was available for 24 of 33 infants. Cardiac function improved significantly between the cooling and the re-warming kphases. This included changes in right ventricular output (127 ± 34 vs 164 ± 47 ml/kg/min, p <0.01) and FAC (20 ± 3 vs 28 ± 2%, p<0.01). Pairwise comparisons for fractional shortening did not show significant changes. From the cooling to the rewarming phase, maximum change was noted in FAC (26.3 ± 9.8%) while minimum change was noted in fractional shortening (median, interquartile range) of 4.6% (1.4, 9.1). Significant correlation between TAPSE and time to peak velocity as a proportion of right ventricular ejection time was noted (r² = 0.68, p <0.001).

CONCLUSIONS:

In infants with moderate to severe HIE, cardiac function evolves during various phases of therapeutic hypothermia. Low output state during cooling may be due to a combination of the disease state (HIE) and cooling therapy.

Keywords

Cardiac function echocardiography perinatal asphyxia therapeutic hypothermia

1. Introduction

Hypoxic ischemic encephalopathy (HIE) affects approximately one to two newborns per 1,000 live births [1]. As a high risk population, these infants often have multi-organ insult. Cardiovascular involvement is a recognized feature, with an incidence ranging from 30% to 82% [2 –4]. In a pre-cooling era study, the severity of cardiac dysfunction was correlated with the degree of encephalopathy [5], raising the possibility that closer monitoring and optimized cardiac function may improve outcomes in other organ systems. Therapeutic hypothermia has been standard of care for infants with perinatal asphyxia in Australia and New Zealand since 2010, and has been shown to reduce mortality without increasing major disability amongst survivors [6, 7]. Impaired auto-regulation (vaso-paralysis) makes ECHO assessments of cardiac function pertinent towards an improved understanding of the cardio-vascular adaptation in infants with HIE, beyond what may be achievable by blood pressure (BP) measurements alone. This is especially true for the right sided hemodynamics as pulmonary hypertension (PH) and/or reduced right heart function may not be readily appreciated clinically. The use of bedside ECHO serves as an optimum, reliable and an easy to administer diagnostic and monitoring tool to achieve this objective.

Limited available data on its cardiovascular effects has noted sinus bradycardia and hemoconcentration [8, 9]. More recently, echocardiographic (ECHO) studies noted a low cardiac output state and reduced myocardial perfusion [1, 10]. A recent single-centre retrospective review of early ECHOs of term infants with moderate or severe HIE noted significantly lower right and left ventricular outputs and elevated biventricular myocardial performance index. Infants who died had a significantly lower diastolic eccentricity index [11]. Serial data, from pre-active cooling, through to cooling and then rewarming phase is lacking.

Based on the limited available data, severe HIE coupled with whole body therapeutic hypothermia has the potential to further complicate an already complex neonatal transitional circulation. The practice of whole body therapeutic hypothermia has focused on the primary outcomes of survival and neurodevelopmental sequelae with limited information on the cardiovascular physiologic measures. Previous studies have described changes in heart rate, BP and the presence of PH [6 , 12–14]. The objectives of this study were to ascertain the magnitude of cardiac function impairments in a cohort of infants with moderate to severe HIE undergoing therapeutic hypothermia. Secondly, we aimed to assess its evolution during various phases of therapeutic hypothermia in a sub-cohort.

2. Methods

Unit electronic database from the period 2010-2016 was used to enlist the study population. Infants with moderate to severe HIE administered therapeutic hypothermia and cardiac function monitored with ECHO were included. Demographic information and clinical data were retrieved, and archived images were accessed. ECHO were performed by a single trained neonatologist and trained echo-technologists from pediatric cardiology during the pre-active cooling phase (T1), cooling phase (T2) and the rewarming phase (T3) using the Vivid 7 advantage cardiovascular ultrasound system (GE Medical Systems, Milwaukee, Wisconsin) with a 7.5-to 10-MHz, high-frequency phased array transducer probe. All images were saved for off-line analysis. Standard M-mode, 2-Dimensional, pulse wave Doppler, continuous wave Doppler, and color Doppler evaluations were performed (Table 1). Previously published normal values for term infants include tricuspid annular peak systolic excursion (TAPSE) >9mm, right ventricular fractional area change (RV FAC) >26%, time to peak velocity/right ventricular ejection time (TPV/RVETc) >0.34 [15 –24]. For studies before 2012, the m-mode was applied to the archived apical 4 chamber segments for the assessment of TAPSE.

Table 1
Summary of hemodynamic assessments

Parameter Technique View Cursor position Comment

RV stroke volume PWD Oblique pulmonary artery view Aligned with the flow, sample at the tips of pulmonary leaflets VTI x CSA indexed to weight

Fractional area change 2D Apical 4 chamber view Include full view of the RV (base to apex) [(RV four-chamber area at end-diastole – RV four-chamber area at end-systole)/RV four-chamber area at end-diastole] x 100%

TAPSE M mode Apical 4 chamber view Lateral tricuspid annulus Measure of longitudinal contractility

TPV/RVETc PWD Oblique pulmonary artery view Aligned with the flow, sample at the tips of pulmonary leaflets 1/(TPV/RVETc) acts as a surrogate for pulmonary vascular resistance

Tricuspid regurgitation CWD Apical 4 chamber view Aligned with the flow to measure maximal velocity Modified Bernoulli’s equation (4TRVmax² +5)

Left ventricular stroke volume PWD Apical 5 chamber view Aligned with the flow, sample at the tips of aortic leaflets VTI x CSA indexed to weight

Fractional shortening M mode Parasternal long axis view Tip of mitral leaflets (LVEDD-LVESD)/LVEDD

Patent ductus arteriosus Colour and PWD High parasternal ductal view Aligned with the ductal flow >30% right to left shunt during the cardiac cycle

Parameter	Technique	View	Cursor position	Comment
RV stroke volume	PWD	Oblique pulmonary artery view	Aligned with the flow, sample at the tips of pulmonary leaflets	VTI x CSA indexed to weight
Fractional area change	2D	Apical 4 chamber view	Include full view of the RV (base to apex)	[(RV four-chamber area at end-diastole – RV four-chamber area at end-systole)/RV four-chamber area at end-diastole] x 100%
TAPSE	M mode	Apical 4 chamber view	Lateral tricuspid annulus	Measure of longitudinal contractility
TPV/RVETc	PWD	Oblique pulmonary artery view	Aligned with the flow, sample at the tips of pulmonary leaflets	1/(TPV/RVETc) acts as a surrogate for pulmonary vascular resistance
Tricuspid regurgitation	CWD	Apical 4 chamber view	Aligned with the flow to measure maximal velocity	Modified Bernoulli’s equation (4TRVmax² +5)
Left ventricular stroke volume	PWD	Apical 5 chamber view	Aligned with the flow, sample at the tips of aortic leaflets	VTI x CSA indexed to weight
Fractional shortening	M mode	Parasternal long axis view	Tip of mitral leaflets	(LVEDD-LVESD)/LVEDD
Patent ductus arteriosus	Colour and PWD	High parasternal ductal view	Aligned with the ductal flow	>30% right to left shunt during the cardiac cycle

PWD-pulse wave Doppler, TPV-time to peak velocity, RVET-right ventricular ejection time, VTI-velocity time integral, RV-right ventricular, CSA-cross-sectional area, 2D-two dimensional, TAPSE-tricuspid annular peak systolic excursion, CWD-continuous wave Doppler, LVEDD-left ventricular end diastolic dimension, LVESD-left ventricular end systolic dimension, TRVmax-tricuspid regurgitation maximal velocity in m/s.

Unit protocol: The Unit practices whole body cooling within six hours of birth when all three of the following criteria are met: (a) gestational age >35 weeks and birthweight >2,000 g, (b) evidence of peri-partum hypoxia–ischemia documenting at least two of: Apgar score ≤5 at 10 min and/or mechanical ventilation or need for resuscitation at 10 min and/or cord pH <7.0 or arterial/venous blood gas pH <7.0 or base deficit ≥12 on sample obtained within 1 hour of birth and (c) moderate or severe hypoxic–ischemic encephalopathy (Sarnat’s). In preparation for active cooling, the infants are passively cooled (no radiant heater or warming blankets used). The aim of therapeutic hypothermia is to maintain the core body temperature between 33 and 34°C for the first 72 hours using the Blanketrol IIITM machine (JLM Accutek Health Care, Homebush, Australia); temperature being measured by a rectal thermistor. Rewarming is achieved over a period of 12 hours. Umbilical arterial and venous catheters are inserted for invasive measurement of BP and to optimize nutrition. The discipline of functional ECHO as an adjunct to clinical decision making and monitoring of critical infants has been prevalent in Australia and New Zealand region for more than 20 years. This is in frequent use at the Unit to assess severity of illness, in addendum to (not as a replacement for) information from clinical signs. When such data, collected in the context of clinical care, is proposed to be used for audit and/or publication, the Institutional requirement is to obtain a ‘Quality Assurance Approval.’ The same has been approved by the Monash Health Research Ethics Committee.

3. Statistics

Data were analyzed using software SPSS v18 and presented as mean ± standard deviation, median (range) and percentages for parametric and non-parametric data. Correlations between variables were assessed by Pearson’s coefficient of correlation. Descriptive statistics were used to characterize the baseline clinical and ECHO characteristics. Analysis of variance testing was used to analyze the serial ECHO changes over time. Pair-wise comparisons of sample means were performed via the Tukey HSD test. Significance was set at two-tailed p <0.05.

4. Results

During the study period, 56 infants with moderate to severe HIE were admitted and administered whole body therapeutic hypothermia. Of these, 33 (59%) had ECHO assessments performed, and were included in the study cohort. Nine had only pre-active cooling (T1) baseline cardiac assessments while the remaining 24 had the same performed during all the three phases. The overall gestation and birthweight of the cohort were 39.6 ± 1.6 weeks and 3306 ± 583 g respectively (Table 2). The first ECHO assessment was done at 5 ± 1 hours of age. Postnatal age at each cardiac assessment in those with serial assessments (n=24) was (T1; 5 ± 1, T2; 40.3 ± 3, T3; 82.7 ± 3.3 hours). No arrhythmias were noted in the study population. A patent ductus arteriosus (PDA) was noted in six (18%) infants (trans-ductal diameter 1.2 ± 0.2 mm) on T1; >30% right to left shunt was noted in four of these infants. By T2, only one infant had a small PDA with no right to left shunt. The PDA was closed in all infants at T3 assessments. None of the infants required volume expansion during rewarming. Six infants (18%) had tricuspid regurgitation (TR) jet velocity ≥2.8m/s on T1 and were administered inhaled nitric oxide. No infant for whom serial assessments were available was administered nitric oxide. Seventeen (51%) were on inotropes (dobutamine=17, additional dopamine=8) at the time of baseline assessments (T1). At T2 and T3, this was administered to (dobutamine = 12, additional dopamine=9) and (dobutamine = 10, additional dopamine = 8) infants, respectively. We analyzed the 12 infants with no inotropic support for whom ECHO data was available in both T1 and T2. The left ventricular output did not show a significant change from T1 to T2 (138 ± 21 to 131 ± 20 ml/kg/min, p=0.6).

Table 2
Demographic and clinical data

Variable N = 33

Gestation (weeks) 39.6 ± 1.6

Birthweight (g) 3306 ± 583

Male gender n (%) 21 (64)

Caesarean section n (%) 18 (55)

Meconium stained liquor n (%) 10 (30.3)

Apgar score at 5 minutes median (range) 3 (0,8)

Resuscitation interventions

• IPPV n (%)
•IPPV + chest compressions n (%)
•IPPV + chest compressions + medications n (%) 31 (94)
20 (61)
13 (40)

Cord/earliest postnatal blood gas parameters

• pH
•Base deficit
•Serum lactate (mmol/L) 6.9 ± 0.25
-18.5 ± 5.6*
17.4 ± .5.5**

Age at start of therapeutic hypothermia (hours) ± 1.5

Survival n (%) 25 (76)

Variable	N = 33
Gestation (weeks)	39.6 ± 1.6
Birthweight (g)	3306 ± 583
Male gender n (%)	21 (64)
Caesarean section n (%)	18 (55)
Meconium stained liquor n (%)	10 (30.3)
Apgar score at 5 minutes median (range)	3 (0,8)
Resuscitation interventions
• IPPV n (%) •IPPV + chest compressions n (%) •IPPV + chest compressions + medications n (%)	31 (94) 20 (61) 13 (40)
Cord/earliest postnatal blood gas parameters
• pH •Base deficit •Serum lactate (mmol/L)	6.9 ± 0.25 -18.5 ± 5.6* 17.4 ± .5.5**
Age at start of therapeutic hypothermia (hours)	± 1.5
Survival n (%)	25 (76)

*n = 29, **n = 31, IPPV-intermittent positive pressure ventilation

Table 3 depicts baseline ECHO parameters for the whole cohort; 25/33 (76%) had very low right or left ventricular outputs (<150ml/kg/min). Compared to previously published gestation specific normative data, 32 (97%) had a low TAPSE (<9 mm) and 23 (70%) had a low RV FAC (<26%) (17, 18). Table 4 and Fig. 1 depict changes in cardiac function measures during the various phases of therapeutic hypothermia. Statistically significant changes between pre-active cooling (T1) phase and cooling phase (T2) were noted for TPV/RVETc and RV FAC (measures reflecting pulmonary vascular resistance [PVR] and RV contractility, respectively). Significant improvements were noted between the cooling (T2) and the re-warming phases (T3). Pairwise comparisons for fractional shortening (FS) did not show significant changes. Table 5 depicts % change in the various measures between T2 and T3; maximum change was noted for FAC. Significant correlation between the measure of RV longitudinal contractility (TAPSE) and TPV/RVETc was noted (Fig. 2). This correlation remained significant during T2 (r=0.6, p=0.001) but not so during T3 (r=0.2, p=0.36). Serum cTnT levels were done in 22 infants during T2, median [interquartile range] was 0.15 [0.08, 1.4µg/L]. Significant correlation was noted between cTnT levels and RV FAC (r= -0.55, p=0.007) and TAPSE (r= - 0.43, p=0.04).

Table 3

Baseline cardiac function assessments in the pre-active cooling (T1) phase

Parameter	N = 33
Temperature °C)	35.7 ± 0.6
Heart rate (beats/min)	124 ± 2
RV output (ml/kg/min)	134 ± 6
RV Fractional Area Change (%)	24 ± 0.5
TAPSE (mm)	7.46 ± 0.11
TPV/RVETc	0.26 ± 0.01
LV output (ml/kg/min)	0.26 ± 0.01
LV Fractional shortening (%)	31.3 ± 0.48

RV-right ventricular, LV-left ventricular, TPV-time to peak velocity, RVET-right ventricular ejection time, TAPSE-tricuspid annular peak; systolic excursion

Table 4

Serial change and pair-wise comparisons in cardiac measures (n=24).

Variable	Pre-cooling phase (T1)	Cooling phase (T2)	Rewarming phase (T3)	p
h Temperature (⁰C)	35.6 ± 0.6	33.6 ± 0.8	36.1 ± 0.35	<0.001
a Heart rate (bpm)	126 ± 10	120 ± 8	130 ± 8	0.001
Right ventricular output (ml/kg/min)	136 ± 36	127 ± 34	164 ± 47	0.005
b TPV/RVETc	0.26 ± 0.06	0.23 ± 0.04	0.3 ± 0.03	<0.001
f Tricuspid Annular Peak Systolic Excursion (mm)	7.4 ± 0.6	6.9 ± 1	8.3 ± 0.5	<0.001
c Right ventricular fractional area change (%)	24 ± 3	20 ± 3	28 ± 2	<0.001
g Left ventricular output (ml/kg/min)	139 ± 31	130 ± 29	172 ± 29	0.0001
d Fractional shortening (%)	31.2 ± 2.7	31.1 ± 2.6	32.8 ± 1.9	0.036

a T1 vs T2 (p NS), T1 vs T3 (p NS), T2 vs T3 (p<0.01), ^e T1 vs T2 (p NS), T1 vs T3 (p<0.05), T2 vs T3 (p<0.01); ^bT1 vs T2 (p<0.05), T1 vs T3 (p<0.05), T2 vs T3 (p<0.01), ^fT1 vs T2 (p NS), T1 vs T3 (p<0.01), T2 vs T3 (p<0.01); ^cT1 vs T2 (p<0.01), T1 vs T3 (p<0.01), T2 vs T3 (p<0.01), ^gT1 vs T2 (p NS), T1 vs T3 (p<0.01), T2 vs T3 (p<0.01); ^dT1 vs T2 (p NS), T1 vs T3 (p NS), T2 vs T3 (p NS), ^hT1 vs T2 (p<0.01), T1 vs T3 (p<0.05), T2 vs T3 (p <0.01); TPV-time to peak velocity, RVET-right ventricular ejection time

Fig.1

Changes in right ventricular fractional area change (%), time to peak velocity/right ventricular ejection time ratio and tricuspid annular peak systolic excursion (mm). Box and whisker plots of each parameter show the range from minimum to maximum values, with 25th to 75th centile (interquartile) ranges and medians indicated.

Table 5

Percentage change in cardiac measures from cooling (T2) to re-warming phase (T3) (n=24, those with serial data).

Variable	Percentage change (mean ± S.D)	Range of change (%)
Heart rate (bpm)	7.46 ± 4.8	0.9 to + 15.6
RV stroke volume (ml/kg)	21.9 ± 5.9	6.1 to + 31
RV fractional area change (%) ^a	26.3 ± 9.8	-2.6 to + 38.6
TAPSE (mm)	17 ± 10.3	2.5 to + 36.7
TPV/RVETc	22 ± 10.5	3.2 to + 46.1
LV stroke volume (ml/kg)	24 ± 5.6	11.5 to + 34.6
Fractional shortening (%) ^a	4.6 (1.4, 9.1)**	-3.2 to + 17.6

TPV-time to peak velocity, RVET-right ventricular ejection time, RV-right ventricular, TAPSE-tricuspid annular peak systolic excursion, LV-left ventricular. ^aone infant noted a reduction, **(median, interquartile range).

Fig.2

Correlation between time to peak velocity/right ventricular ejection time ratio and tricuspid annular peak systolic excursion (mm) at baseline (T1).

5. Discussion

Infants with HIE are critically ill with multi-organ system dysfunction and the cardiac impairment may have a significant effect on circulation and end-organ perfusion. While HIE itself is noted to cause cardiac dysfunction and reduced cardiac output, whole body hypothermia may potentially slow recovery. In this study we noted significant impairments in bi-ventricular outputs; RV specific parameters (FAC and TAPSE) indicating it to be severely affected. Cardiac performance evolved over time, significantly improving during the rewarming phase.

5.1 Right ventricular/pulmonary effects of perinatal asphyxia

Two major, often co-existent patterns of myocardial dysfunction are recognized in the infants with HIE. These include depressed systemic function and moderate to severe PH accompanied by RV dysfunction [1 , 26]. Normal RV systolic function is critical for adequate pulmonary blood flow; the impairment may be either cardiogenic in origin or related to increased PVR or both. Compromised RV output induces ventilation-perfusion mismatch and reduces LV preload. This compounds the direct effect of hypoxia/ischemia on the LV function, reducing systemic blood flow and subsequently cerebral oxygen delivery. A reduced RV FAC, cardiac output & TAPSE indicated RV impairment and a significant correlation between TAPSE and TPV/RVETc indicated the influence of pulmonary afterload.

Bedside ECHO is central to the assessment and management of this clinically important and dynamic RV ventricular-arterial coupling. Hypoxia and acidosis contribute to raise pulmonary pressures, and clinically significant PH is a known complication of HIE [25 –28]. The course of raised pulmonary pressures in the infants with HIE is variable and may not always be congruent with the clinical presentation [29, 30]. In a previous study, the inspired oxygen fraction had to be increased by a median of 0.14 to maintain oxygenation during cooling (with a few requiring 100% oxygen, an effect probably attributable to PH) [12]. This reversed with rewarming. Given PH may be difficult to discern on clinical signs alone, bedside ECHO becomes integral for diagnosis, monitoring and tailoring appropriate therapy. Tricuspid regurgitation and bidirectional ductal shunting in some of our infants indicated presence of PH.

5.2 Left ventricular/systemic effects of perinatal asphyxia

BP as a product of cardiac output and vascular resistance is possibly affected by competing forces of vaso-paralysis and hypothermia induced peripheral vasoconstriction. The systemic effects can be ascertained by changes in BP, electrocardiographic changes or more recently, ECHO signs of low output. The former (BP and electrocardiography) indicated a high incidence of up to 80% [2 –4]. Wood and Thoresen highlighted that the constriction of the peripheral venous system and sedation may reduce venous return and preload [31]. Evidently, the systemic effects in infants with HIE are complex and multi-factorial, and while continuous BP assessments are readily available at the bedside, ECHO may provide further information.

Doppler ECHO facilitates non-invasive assessments of cardiac function which have been validated against invasive measures in neonates [32]. A number of recent studies in infants with HIE have evaluated ECHO signs and serum cTnT levels (as biochemical evidence of myocardial injury) and noted significant correlation between the two [10 , 34]. Some ECHO measures are more informative than others. Comparable FS between infants with HIE and control infants has been noted by other investigators too, indicating it to be less sensitive [25]. Tissue Doppler imaging has greater sensitivity to assess LV systolic function compared to FS and stroke volume [33]. Using deformation imaging Nestaas et al noted that strain-rate indices in the hypothermia treated cohort improved significantly after rewarming and were not significantly different from the healthy controls [35]. Conventional ECHO however, remains the bedrock of cardiac assessments in this population, and a recent cohort noted very low cardiac output (<150ml/kg/min) in approximately 75% of infants [28]. We noted significantly impaired cardiac function as part of HIE related multi-organ insult.

5.3 Evolution of cardiac function during hypothermia

Changes in peripheral vasoconstriction, release of catecholamines as well as rheological properties (viscosity) of blood attributable to hypothermia may be important additional factors [36]. An increase in peripheral resistance (afterload) related to higher blood viscosity, increases with decreasing body temperature [37, 38]; increased peripheral vascular resistance and cardiac afterload have been noted in the cooled porcine model [39]. In animal models, hypothermia of 34-35⁰C range (similar to that recommended for infants with HIE) also decreased LV contractility and cardiac output [40, 41].

Serial data documenting the evolution of cardiovascular function during different phases of therapeutic hypothermia are lacking. In a cross-sectional study of infants with HIE receiving therapeutic hypothermia, Sehgal et al., noted low cardiac output and superior vena cava flow [10]. A recent retrospective ECHO study comparing cooled HIE infants and normal controls in the initial 24 hours noted significantly cardiac function impairments [11]. Infants were not serially followed up in either of these studies. Gebauer and colleagues studied seven infants with HIE during whole body hypothermia and passive rewarming [1]. Cardiac output was reduced to 67% of the post-hypothermic levels with a consistent increase during re-warming. They noted lower cardiac output during hypothermia, compared with normal values for stroke volume and cardiac output for healthy newborns. We noted that cardiac function improved during the transition from cooling to the rewarming phase.

In light of these findings, it begs the question whether the evolution we documented is simply an adaptive response? Given one purpose of whole body therapeutic hypothermia is to reduce the metabolic demand; could these changes reflect cardiac adaptation to the original insult and the ongoing therapeutics? A prospective study assessing cardiac output, cerebral blood flow and neurologic outcomes may be best placed to answer these questions. The study has the usual limitations of retrospective studies. While the overall number of infants in this study is small, it is still the largest cohort of HIE infants with serial ECHO findings. Lack of ECHO in all the infants with moderate to severe HIE born during the study period, and the availability of serial ECHO data in only a sub-set are other limitations. Nevertheless, the study does shed new light on newer measures to discern the subtleties of the evolution of cardiac function in a critically ill population, administered a standard of care therapy.

Disclosures

No financial disclosures or conflicts and no grants or funding relevant to this research.

The research was conducted in accordance with the ethical standards of all applicable national and institutional committees and the World Medical Association’s Helsinki Declaration. The research was approved by the Monash Health Research Ethics Committee. Individual patient consent not applicable as retrospective data.

Footnotes

Acknowledgments

None.

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